Disclosed is a hemisulfate salt of N-(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate, as well as crystalline forms thereof. Also disclosed are at least one pharmaceutical composition comprising the hemisulfate salt of N-(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate and at least one method of using the hemisulfate salt of N-(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate in the treatment of a CGRP-related disorder, such as migraine headaches and asthma.
The compound, N-(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl-4-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate, has the structure of formula I:
and is referred to herein as “Compound (I)”. Compound (I), processes to prepare Compound (I), and methods of treatment employing Compound (I) are disclosed in U.S. Patent Publication 2011/0251223 A1. This reference is assigned to the present assignee and is incorporated herein by reference in its entirety.
The usefulness of an oral formulation is dependent upon, among other things, the degree to which the active agent is bioavailable and consistency in bioavailability among patients. The bioavailability of orally administered drugs is often affected by various factors including, for example, the solubility of the drug in the gastrointestinal tract, the stability of the drug in the gastrointestinal tract, and drug absorption in the gastrointestinal tract. Further, these factors may be affected by coadministration of other drugs and/or the intake of food, which may lead to variability in the bioavailability of orally administered drug. Furthermore, rapid in vivo dissolution of the active agent is also required to provide rapid treatment of conditions such as migraine headaches.
The dissolution rate of Compound (I) is dependent on the pH of the aqueous medium. Compound (I) has a higher dissolution rate at pH values of 1 and 5 than at a pH value of 7. In the oral administration of Compound (I), the dissolution rate and hence the bioavailability of Compound I can be affected by the pH of the stomach contents. The normal pH of the stomach is 1.2 to 1.8 according to C. J. Perigard, Clinical Analysis, Chapter 32, in Remington: The Science and Practice of Pharmacy 20th Edition, A. R. Gennaro, editor; 2000, Lippinocott Williams & Wilkins, Baltimore, Md. However, patients often take other medications that can raise the pH of the stomach, including antacids, proton pump inhibitors, and H2-receptor antagonists such as famotidine, which can lower the dissolution rate of Compound (I).
Typically, in preparing a pharmaceutical composition, a form of the active ingredient is sought that has a balance of desired properties, such as, for example, dissolution rate, solubility, bioavailability, and/or storage stability. For example, a form of the active ingredient is sought having sufficient stability, solubility, and bioavailability to prevent the sufficiently soluble and bioavailable form from converting during the manufacture, preparation, and/or storage of the pharmaceutical composition to another form having an undesirable solubility and/or bioavailability profile. For example, a form of the active ingredient is sought that is stable and has low hygroscopicity at ambient temperature and humidity conditions.
In addition, a form of the active ingredient may also be sought that permits the active ingredient to be produced by a process that is amendable to large-scale production. In such a process, it is desirable that active ingredient is in a form that allows facile isolation and/or purification of the active ingredient, for example, by filtration, as well as easy drying.
Further, as production economics are important, it is desirable to avoid the use of higher cost materials, whenever possible, in the preparation of the form.
Applicants have found a hemisulfate salt of Compound (I) that surprisingly reduces the variability in the bioavailability of Compound (I), provides consistency in bioavailability among patients, and/or increases the bioavailability of Compound (I) to the patient. Further, Applicants have also found a crystalline form of the hemisulfate salt of Compound (I) that surprisingly reduces the variability in the bioavailability of Compound (I), provides consistency in bioavailability among patients, and/or increases the bioavailability of Compound (I) to the patient. The hemisulfate salt of Compound (I) and the crystalline form thereof, surprisingly afford a balance of properties sought in a pharmaceutical composition. The present invention is also directed to other important aspects.